Certain nuclei in the phylogenetically older regions of the brain are exquisitely sensitive to several chemically unrelated neurotoxicants. Many of these chemicals perturb mitochondrial glutathione (GSH) homeostasis and energy metabolism. It is hypothesized that regional differences in astrocytic mitochondrial glutathione homeostasis render specific populations of astrocytes in the brainstem vulnerable to chemically-induced energy deprivation syndromes. The regional and cellular distribution of lesions produced by chemicals such as 1,3- dinitrobenzene (DNB), nitroimidazoles, and NAD(P)H antimetabolites is similar to those observed in the brainstem of humans and livestock afflicted with an "Acute Energy Deprivation Syndrome" (AEDS) or idiopthic perturbation of regional mitochondrial function. Early phases of these chemically-induced syndromes include swelling of astrocytes and their mitochondria initially confined to selected regions of the brainstem which have a high requirement for energy metabolism. Chemicals which produce AEDS, including aromatic nitrocompounds such as DNB, alter cellular GSH status. However, glutathione is not equally distributed in neural cells or their subcellular compartments. Although astrocytes contain high total levels of GSH, their mitochondrial (mt) pools are particularly vulnerable to depletion. Compelling biochemical evidence suggests that the mt enzyme lipoamide dehydrogenase, a key component of pyruvate, alpha-ketoglutarate and succinate dehydrogenases, is also a nitroreductase. Single-electron reduction of nitrocompounds to the reactive nitroxyl radical may initiate futile reduction of oxygen, oxidative shifts in mt redox potential, oxidation of GSH and disruption of mt-energy metabolism. Regional, cellular differences in mitochondrial GSH homeostasis might, therefore, render populations of astrocytes vulnerable to oxidative stress by nitrocompounds and other oxidative stressors. The hypothesis will be tested by addressing the following specific questions: 1. What are the differences in regional, cellular and subcellular glutathione status and homeostasis? 2. Does modulation of cellular antioxidant status alter regional mt- susceptibility to neurotoxicant-induced oxidative stress? 3. Does mt- metabolic activation of neurotoxicants to reactive species affect gluthathione homeostasis, energy metabolism and physiological function of mitochondria in specific astrocyte populations? Model neurotoxicants which produce distinct, astocytic lesions confined to vulnerable brainstem nuclei will be used to determine the role of mtGSH in the etiology of AEDS. It is anticipated that the proposed experiments will provide information on basic mechanisms of oxidative stress which contribute to the loss of specific brain cell populations following exposure to neurotoxic chemicals in the environment.